This invention relates to novel peptide derivatives and more particularly to tetrapeptide derivatives having activity as inhibitors of platelet aggregation.
Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formation in the blood clotting mechanism.
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gpIIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating platelet thrombus formation.
It is also known that another large glycoprotein named fibronectin, which is a major extracellular matrix protein, interacts with fibrinogen and fibrin, and with other structural molecules such as actin, collagen and proteoglycans. Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. See U.S. Pat. Nos. 4,517,686; 4,589,881; and 4,661,111. These polypeptides include an internal amino acid sequence Arg-Gly-Asp-Ser. Certain relatively short peptide fragments from the same molecule were found to promote cell attachment to a substrate when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form. See U.S. Pat. Nos. 4,578,079 and 4,614,517. These peptides were defined as
X-Arg-Gly-Asp-R-Y PA1 wherein X=H or amino acid, PA1 R=Thr or Cys; PA1 X-Arg-Gly-Asp-Ser-Y PA1 wherein X=H or amino acid, PA1 Y=OH or amino acid. PA1 Arg-Gly-Asp-Val or PA1 Arg-Gly-Asp-Ser at the C-terminal. PA1 X-Gly-Asp-Y (I) ##STR1## Z=H, NH.sub.2 or NH-Acyl, n=1 to 4, ##STR2## R.sub.1 =H, alkyl, phenyl or phenylalkyl, R.sub.2 =H, COOH, CONH.sub.2, COCH.sub.3, CH.sub.2 OH, CH.sub.2 NH.sub.2, C(NH)CH.sub.3 or C(NH)NH.sub.2, PA1 R.sub.3 =phenyl, biphenyl or naphthyl, each substituted with 1 to 3 alkyl or alkoxy groups, or an unsubstituted naphthyl, biphenyl or pyridyl group, PA1 m=0 to 2,
and
In U.S. Pat. No. 4,683,291, inhibition of platelet function is disclosed with synthetic peptides designed to be high affinity antagonists of fibrinogen binding to platelets. These synthetic peptides have up to 16 amino acid residues with
Similar synthetic peptides which contain the Arg-Gly-Asp sequence and their use as inhibitors of fibrinogen binding to platelets are disclosed by Kloczewiak et al., Biochem. 23, 1767-1774 (1984); Plow et al., Proc. Natl. Acad. Sci. 82, 8057-8061 (1985); Ruggeri et al., Ibid. 83, 5708-5712 (1986); Ginsberg et al., J. Biol. Chem. 260 (7), 3931-3936 (1985); and Haverstick et al., Blood 66 (4), 946-952 (1985).